Epigenetic inheritance in germline stem cell lineage Abstract: Stem cells are unique in their abilities to self-renew and give rise to various differentiated cells. Many types of stem cells undergo asymmetric cell division to generate a self-renewed stem cell and a daughter cell committing for differentiation. Mis-regulation of stem cell asymmetric division may lead to tumorigenesis or tissue dystrophy. Of all known types of adult stem cells, germ cells are the most immortal, due to their abilities to produce the next generation of an entire organism upon fertilization. The Drosophila male germline stem cells (GSCs) are among the best characterized stem cell systems. Male GSCs can be identified by their distinct anatomical positions and morphological features within the fly testis. This makes it feasible to study these stem cells at single cell resolution, which allows direct comparisons between GSCs and their daughter cells, the gonialblasts. Understanding the molecular mechanisms underlying GSC asymmetric cell division is of broad interest to cancer biology, reproductive biology, as well as regenerative medicine. I hypothesized that epigenetic difference between sister chromatids contributes to stem cell asymmetric division. It has been known for long time that epigenetic changes are heritable. However, except for DNA methylation, little is known about the molecular mechanisms of epigenetic inheritance. I propose to use molecular, genetic and cell biology tools to investigate in real time whether Drosophila male GSCs preserve a particular chromatin structure by inheriting a unique set of "epigenetic codes";the regulatory pathways that lead to such an inheritance;and the potential abnormalities that arise from the mis-regulation of epigenetic inheritance. PUBLIC HEALTH RELEVANCE: Stem cells are of great value for both biomedical research and regenerative medicine. To effectively utilize stem cells in therapeutic applications to cure many human diseases, we have to thoroughly understand the molecular mechanisms underlying stem cell self-renewal abilities. The proposed work will explore whether stem cells maintain themselves by inheriting a particular set of proteins;and whether by doing so, stem cells keep a specific group of genes active while the rest to be silent. We propose to use both state-of-the-art cell biology tools to visualize such process in real time and molecular genetic strategies to explore how mis-regulation of it may lead to diseases.